This project, which is devoted to the study of both forms of immune complex (IC) mediated glomerulonephritis (GN): GN due to deposition of circulating IC or GN due to in situ IC formation, has four major investigative themes: 1) The erythrocyte/leukocyte-IC clearing mechanism. We have clear evidence that erythrocytes, and perhaps leukocytes, play a critical role in removing pathogenic IC safely from the blood. Erythrocytes intercept IC in the vascular space causing the IC to bind to the erythrocyte until the erythrocyte passes through liver or spleen where the IC are stripped from the erythrocyte deposited in liver or spleen and the erythrocyte returned to the circulation. By contrast, IC on erythrocytes do not deposit in glomeruli. Thus, the proper function of this mechanism may be critically important in preventing GN. 2) Glomerular subepithelial in situ IC formation. This process, which leads to membranous GN, requires that IgG diffuse from the glomerular capillary lumen to the subepithelial space to combine with antigen. To discover means to prevent the flux of IgG to the subepithelial space we will study the Lewis rat which has an antigen in the subepithelial space to which antibody can be readily raised. Thus, labelled IgG aimed at antigen in the subepithelial space will be the immunologic "probe" to search for factors which modulate this essential step in the pathogenesis of membranous GN. 3) Splanchnic blood flow and the removal of circulating IC from blood. We have evidence that IC uptake by liver and spleen should be strongly flow dependent. We will test that hypothesis and, if substantiated, will explore the usefulness of regulation of splanchnic blood flow in the control of IC-mediated diseases. 4) Glomerular avidity for circulating immune complexes. We have evidence that glomeruli must be altered in some way to permit the high rate of IC trapping necessary to induce GN. We suspect that fever, exercise, endotoxin and parathyroid hormone may be among such factors. Using techniques we have described previously, we will search for factors which regulate the glomerular uptake of circulating IC.